Structural mechanism of the Wnt-receptor interaction
| Project/Area Number |
17H01420
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Structural biochemistry
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥43,030,000 (Direct Cost: ¥33,100,000、Indirect Cost: ¥9,930,000)
Fiscal Year 2019: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2018: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2017: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
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| Keywords | Wntシグナル / Ｘ線結晶構造解析 / 受容体 / 蛋白質間相互作用 / 蛋白質ー脂質間相互作用 / X線結晶構造解析 |
|---|
| Outline of Final Research Achievements |
Wnt/beta-catenin signaling plays fundamental roles in organogenesis, tissue regeneration, and cancer, but current understanding of its molecular mechanism is limited due to the lack of high resolution structural information of mammalian Wnt proteins. Through this research project, we determined a 2.8 angstrome-resolution crystal structure of human Wnt3 in complex with its receptor Frizzled 8 for the first time. Furthermore, by using the RaPID system, we have performed in vitro selection against mouse Wnt3a to discover macrocyclic peptide binders, resulting in a peptide (WAp-D04) that can inhibit the receptor-mediated signaling processin cells. This work represents the first instance of molecules capable of inhibiting Wnt signaling through direct interaction with a Wnt protein, a molecular class for which targeting has been challenging due its highly hydrophobic nature.
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| Academic Significance and Societal Importance of the Research Achievements |
Wntシグナルは多細胞動物の発生・形態形成に必須なだけでなく、その異常はがんを含む様々な疾患に関わり、さらにはWntが組織幹細胞の生存と増殖に必須な増殖因子であることから再生医療を進めるためにも非常に重要な蛋白質である。本研究では、世界初のヒトWnt3の結晶構造解析により、これまで不明であったこの重要なシグナル伝達の分子メカニズムの原子レベルでの解明に大きく前進しただけで無く、がんに対する医薬のリードとなり得る化合物を得ることにも成功した。
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Report
(4 results)
Research Products
(61 results)
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[Journal Article] Structural basis of sarco/endoplasmic reticulum Ca2+-ATPase 2b regulation via transmembrane helix interplay2019
Author(s)
Michio Inoue, Nanami Sakuta, Satoshi Watanabe, Yuxia Zhang, Kunihito Yoshikaie, Yoshiki Tanaka, Ryo Ushioda, Yukinari Kato, Junichi Takagi, Tomoya Tsukazaki, Kazuhiro Nagata, Kenji Inaba
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Journal Title
Cell Reports
Volume: 27
Issue: 4
Pages: 1221-1230
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor.2019
Author(s)
Sakai K, Passioura T, Sato H, Ito K, Furuhashi H, Umitsu M, Takagi J, Kato Y, Mukai H, Warashina S, Zouda M, Watanabe Y, Yano S, Shibata M, Suga H, Matsumoto K
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Journal Title
Nature Chemical Biology
Volume: 15
Issue: 6
Pages: 598-606
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach.2019
Author(s)
Jangphattananont N, Sato H, Imamura R, Sakai K, Terakado Y, Murakami K, Barker N, Oshima H, Oshima M, Takagi J, Kato Y, Yano S, Matsumoto K
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Journal Title
International Journal of Molecular Sciences
Volume: 12
Issue: 12
Pages: 2955-2955
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression.2018
Author(s)
Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K, Fujii M, Ohta Y, Matano M, Nanki K, Kawasaki K, Takahashi S, Sugimoto S, Iwasaki E, Takagi J, Itoi T, Kitago M, Kitagawa Y, Kanai T, Sato T.
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Journal Title
Cell Stem Cell.
Volume: 22
Issue: 3
Pages: 454-467
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors2017
Author(s)
Saito Fumiji、Hirayasu Kouyuki、Satoh Takeshi、Wang Christian W.、Lusingu John、Arimori Takao、Shida Kyoko、Palacpac Nirianne Marie Q.、Itagaki Sawako、Iwanaga Shiroh、Takashima Eizo、Tsuboi Takafumi、Kohyama Masako、Suenaga Tadahiro、Colonna Marco、Takagi Junichi、Lavstsen Thomas、Horii Toshihiro、Arase Hisashi
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Journal Title
Nature.
Volume: 552
Issue: 7683
Pages: 101-105
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] The activated conformation of integrin β7 as a target for multiple myeloma-specific chimeric antigen receptor T cell therapy.2017
Author(s)
Hosen N, Matsunaga Y, Hasegawa K, Matsuno H, Nakamura Y, Makita M, Watanabe K, Yoshida M, Satoh K, Morimoto S, Fujiki F, Nakajima H, Nakata J, Nishida S, Tsuboi A, Oka Y, Manabe M, Ichihara H, Aoyama Y, Mugitani A, Nakao T, Hino M, Uchibori R, Ozawa K, Baba Y, et al.
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Journal Title
Nat. Med.
Volume: 23
Issue: 12
Pages: 1436-1443
DOI
Related Report
Peer Reviewed
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[Journal Article] Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c.2017
Author(s)
Meng H, Yamashita C, Shiba-Fukushima K, Inoshita T, Funayama M, Sato S, Hatta T, Natsume T, Umitsu M, Takagi J, Imai Y, Hattori N.
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Journal Title
Nat Commun
Volume: 8
Issue: 1
Pages: 15500-15500
DOI
Related Report
Peer Reviewed / Open Access
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